Maximum lifespan of each species is genetically determined, but within species large variations still occur. We suggest that in man, HLA, the Major Histocompatibility Complex (MHC) is responsible for those differences. This hypothesis is based on observations that H-2 (MHC of mice) has a significant effect on aging in terms of mean lifespan and even 10th decile survival. Previous HLA studies were limited and have yielded conflicting results. Associations can only be revealed if a sufficiently large and ethnically homogeneous population is investigated for age at time of death and if these data are correlated with the results of extensive HLA typings. Our hypothesis also states that there is an association between HLA phenotypes and the disease spectrum of an individual. Our hypotheses need special requirements which are fulfilled by our local conditions. The municipality of Leiden currently has a population just over 100,000 with almost 1,200 in the "oldest old" group. All relevant demographic information are available from the computerized civic registry which is updated twice weekly. HLA typing will cover the HLA-A, B, C, DR and DQ specificities. The immune status of the study population will be assessed by investigating four major age-related immune parameters: T and NK cells, monoclonal gammapathies and autoantibodies. The control group will consist of blood bank donors with similar ethnic backgrounds and from an age group with minimal mortality. Clinical information on the aged population will be obtained from their GP's, nursing homes and local hospitals. Actuarial analysis of the "oldest old" group indicates a 50% probability of death in three years. Consequently, a follow-up period of that length is an integral part of the research plan. Our results may allow us to determine the correlation of the human MHC with longevity and with health status. They may increase our insight into the process of aging. The results of the analyses of mortality may enable us to define high-risk groups in terms of their HLA phenotypes and their immune status. That information may make it possible to selectively apply preventive and/or intervention measures.